Identfication of Potent LXRβ-Selective Agonists without LXRα Activation by In Silico Approaches
Abstract
:1. Introduction
2. Results and Discussion
2.1. Results of Dataset Division by Kohonen Map
2.2. MLR Model Results of LXRβ Activity
2.3. QSAR Model Results of LXRα Activity
2.4. Interpretation of the Descriptors
2.5. Screening New Highly LXRβ-Selective Agonists
2.6. Molecular Docking Study
3. Materials and Methods
3.1. Dataset Division
3.2. Stepwise Multiple Linear Regression (SW-MLR)
3.3. Model Validation
3.4. Screening News LXRβ-Selective Agonists
3.5. Molecular Docking Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Descriptor | Chemical Meaning | Coefficient | Standard Coefficient | VIF | p-Value |
---|---|---|---|---|---|
vsurf_IW2 | Hydrophilic integy moment | −0.777 | −0.592 | 2.246 | 0.000 |
SMR_VSA6 | Sum of vi such that Ri is in (0.485,0.56] | 0.007 | 0.325 | 1.232 | 0.000 |
glob | Globularity, or inverse condition number (smallest eigenvalue divided by the largest eigenvalue) of the covariance matrix of atomic coordinates. | −1.236 | −0.668 | 1.779 | 0.000 |
GCUT_SLOGP_2 | The GCUT descriptors using atomic contribution to logP | 4.560 | 0.687 | 2.785 | 0.000 |
E_strain | Local strain energy | −60.185 | −0.315 | 1.196 | 0.000 |
dipoleX | The x component of the dipole moment | −0.189 | −0.358 | 1.240 | 0.000 |
AM1_LUMO | The energy (eV) of the Lowest Unoccupied Molecular Orbital calculated using the AM1 Hamiltonian | −0.247 | −0.397 | 2.712 | 0.003 |
vsurf_IW5 | Hydrophilic integy moment | 0.154 | 0.284 | 1.790 | 0.007 |
vsurf_DD13 | Contact distances of vsurf_DDmin | 0.016 | 0.212 | 1.192 | 0.013 |
Constant | 5.087 |
Training Set | Test Set | ||||||
---|---|---|---|---|---|---|---|
QSARModel | R2train | RMSEtrain | F | Q2LOO | RMSELOO | R2test | RMSEtest |
LXR beta | 0.837 | 0.118 | 17.235 | 0.715 | 0.156 | 0.843 | 0.232 |
LXR alpha | 0.968 | 0.045 | 44.068 | 0.895 | 0.081 | 0.914 | 0.155 |
Descriptor | Chemical Meaning | Coefficient | Standard Coefficient | VIF | p-Value |
---|---|---|---|---|---|
GCUT_SLOGP_2 | The GCUT descriptors using atomic contribution to logP | 8.952 | 1.539 | 4.862 | 0.000 |
vsurf_DD12 | Contact distances of vsurf_DDmin | 0.024 | 0.366 | 1.348 | 0.000 |
Q_VSA_POS | Total positive van der Waals surface area | 0.005 | 0.673 | 2.161 | 0.000 |
SlogP_VSA2 | Sum of vi such that Li is in (−0.2,0] | 0.023 | 0.813 | 4.763 | 0.000 |
E_ang | Angle bend potential energy | −0.019 | −0.325 | 2.126 | 0.000 |
pmiY | y component of the principal moment of inertia | 4.808 × 10−5 | 0.209 | 1.468 | 0.001 |
dipoleY | The y component of the dipole moment | 0.164 | 0.281 | 1.408 | 0.000 |
vsurf_DW12 | Contact distances of vsurf_EWmin | −0.019 | −0.203 | 1.467 | 0.001 |
BCUT_SMR_0 | The BCUT descriptors using atomic contribution to molar refractivity | 34.772 | 0.351 | 2.546 | 0.000 |
SlogP_VSA3 | Sum of vi such that Li is in (0,0.1] | 0.005 | 0.238 | 1.590 | 0.000 |
vsurf_CW6 | Capacity factor | −4.271 | −0.273 | 3.370 | 0.003 |
Q_VSA_FPPOS | Fractional positive polar van der Waals surface area | −1.339 | −0.144 | 1.810 | 0.024 |
Constant | 83.858 |
No. of Test | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | |
---|---|---|---|---|---|---|---|---|---|---|---|
LXRβ model | R2train | 0.185 | 0.182 | 0.155 | 0.257 | 0.282 | 0.208 | 0.126 | 0.244 | 0.155 | 0.241 |
Q2LOO | 0.063 | 0.006 | 0.018 | 0.001 | 0.037 | 0.015 | 0.081 | 0.002 | 0.047 | 0.003 | |
LXRα model | R2train | 0.259 | 0.174 | 0.288 | 0.287 | 0.334 | 0.298 | 0.25 | 0.264 | 0.258 | 0.287 |
Q2LOO | 0.033 | 0.097 | 0.086 | 0.009 | 0.015 | 0.039 | 0.023 | 0.016 | 0.032 | 0.027 |
AM1_LUMO | GCUT_SLOGP_2 | E_strain | dipoleX | SMR_VSA6 | vsurf_DD13 | vsurf_IW2 | vsurf_IW5 | Glob | |
---|---|---|---|---|---|---|---|---|---|
BCUT_SMR_0 | 0.031 | −0.255 | 0.254 | 0.199 | −0.243 | −0.172 | 0.075 | −0.069 | −0.063 |
GCUT_SLOGP_2 | −0.055 | 0.014 | 0.066 | −0.194 | −0.371 | 0.090 | 0.226 | −0.133 | 0.110 |
Q_VSA_FPPOS | −0.242 | −0.315 | 0.072 | −0.008 | −0.041 | 0.258 | −0.178 | −0.184 | −0.117 |
Q_VSA_POS | −0.017 | 0.279 | −0.182 | −0.164 | 0.240 | 0.113 | −0.202 | −0.012 | 0.013 |
E_ang | −0.069 | −0.431 | 0.007 | −0.030 | 0.173 | 0.531 | 0.148 | −0.261 | −0.361 |
dipoleY | −0.216 | 0.045 | −0.168 | −0.189 | 0.051 | −0.001 | −0.062 | −0.086 | 0.254 |
pmiY | 0.204 | −0.159 | −0.195 | −0.098 | −0.020 | 0.110 | 0.216 | 0.067 | −0.353 |
SlogP_VSA2 | 0.029 | −0.166 | −0.012 | 0.083 | 0.210 | 0.054 | −0.076 | 0.051 | −0.347 |
SlogP_VSA3 | −0.155 | 0.246 | 0.095 | −0.032 | −0.236 | 0.015 | 0.026 | 0.082 | 0.085 |
vsurf_CW6 | −0.056 | 0.002 | 0.352 | −0.231 | −0.116 | −0.127 | −0.137 | −0.156 | 0.201 |
vsurf_DD12 | −0.564 | 0.005 | 0.161 | 0.067 | −0.400 | 0.226 | 0.243 | 0.060 | −0.211 |
vsurf_DW12 | 0.116 | −0.075 | −0.046 | −0.324 | 0.099 | −0.099 | −0.092 | −0.304 | −0.091 |
Name | R1 | R2 | R3 | R4 | X | Predicted pEC50 Values | ||
---|---|---|---|---|---|---|---|---|
LXRβ | LXRα | Docking Scores | ||||||
ZINC55084484 | H | H | H | H | CO | 7.343 | −1.901 | −7.713 |
N1 | 2,2,2-trifluoroethylamino | H | H | Cl | CH2 | 8.497 | −1.911 | −11.205 |
N2 | 2,2,2-trifluoroethylamino | H | H | H | CH2 | 8.390 | −2.076 | −9.394 |
N3 | 2,2,2-trifluoroethylamino | Cl | H | H | CH2 | 8.429 | −1.730 | −9.757 |
N4 | 2,2,2-trifluoroethylamino | F | H | H | CO | 8.328 | 0.215 | −10.236 |
N5 | propionyloxy | H | H | H | CO | 8.148 | −0.753 | −9.528 |
N6 | 2,2,2-trifluoroethylamino | H | propionyloxy | H | CH2 | 7.932 | −0.9524 | −9.323 |
N7 | propionyloxy | H | propionyloxy | H | CO | 7.923 | −0.905 | −9.177 |
N8 | 2,2,2-trifluoroethylamino | F | H | H | CH2 | 8.178 | −1.760 | −10.068 |
N9 | 2,2,2-trifluoroethylamino | H | propionyloxy | H | CO | 8.111 | −1.211 | −10.321 |
Name | Predicted pEC50 Values | Weight | a_acc | a_don | logP(o/w) | |
---|---|---|---|---|---|---|
LXRβ | LXRα | |||||
ZINC55084484 | 7.343 | −1.901 | 347.459 | 4 | 1 | 1.218 |
N1 | 8.497 | −1.911 | 465.968 | 4 | 2 | 2.757 |
N2 | 8.390 | −2.076 | 431.523 | 4 | 2 | 2.128 |
N3 | 8.429 | −1.730 | 465.968 | 4 | 2 | 2.718 |
N4 | 8.328 | 0.215 | 463.496 | 3 | 2 | 1.777 |
N5 | 8.148 | −0.753 | 420.53 | 4 | 1 | 1.376 |
N6 | 7.932 | −0.9524 | 503.586 | 5 | 2 | 2.573 |
N7 | 7.923 | −0.905 | 492.593 | 5 | 1 | 1.821 |
N8 | 8.178 | −1.760 | 449.513 | 4 | 2 | 2.279 |
N9 | 8.111 | −1.211 | 517.569 | 4 | 2 | 2.071 |
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Chen, M.; Yang, F.; Kang, J.; Gan, H.; Yang, X.; Lai, X.; Gao, Y. Identfication of Potent LXRβ-Selective Agonists without LXRα Activation by In Silico Approaches. Molecules 2018, 23, 1349. https://doi.org/10.3390/molecules23061349
Chen M, Yang F, Kang J, Gan H, Yang X, Lai X, Gao Y. Identfication of Potent LXRβ-Selective Agonists without LXRα Activation by In Silico Approaches. Molecules. 2018; 23(6):1349. https://doi.org/10.3390/molecules23061349
Chicago/Turabian StyleChen, Meimei, Fafu Yang, Jie Kang, Huijuan Gan, Xuemei Yang, Xinmei Lai, and Yuxing Gao. 2018. "Identfication of Potent LXRβ-Selective Agonists without LXRα Activation by In Silico Approaches" Molecules 23, no. 6: 1349. https://doi.org/10.3390/molecules23061349